The current application proposes to investigate the genetic control of autoantibody production in experimental and spontaneous systemic lupus erythematosus in mice. It will concentrate on two genetic loci which play a major role in general immunity: immunoglobulin and major histocompatibility complex. The proposed work is based on previous observations that certain alleles at these loci confer particular susceptibility to autoimmunity. The specific aims are outlined as follows: 1. How does the Igh(b) allotype favor autoantibody production? a. Does the b-allotype effect extend to additional isotypes and autoantibody specificities? b. Is b-allotype skewing specific for autoantibodies? c. Does b-allotype skewing of autoantibodies occur in other strain combinations? d. Does the allotype effect result from the V-region or C-region? e. Is somatic mutation greater in the b allotype than in the a allotype? f. Are there constant region effects? g. Does the light-chain locus also have an effect on autoantibody production? 2. What are the relative roles of I-E version I-A recognition in the autoimmune graft-versus-host reaction (GVH)? a. Are there quantitative differences in I-A versus I-E recognition? b. Are there differences in fine specificity for ANAs induced by disparity at I-E versus I-A? c. Are there differences in glomerulonephritis between I-A- and I-E-mediated GVH disease? d. How is GVH disease down regulated? These proposed studies will further the mechanistic understanding of the genetics of autoimmunity. Such knowledge will help uncover the basic immunoregulatory dysfunctions that produce systemic autoimmunity and will eventually allow the development of rational therapy.